1. Field of the Disclosure
The present disclosure relates generally to pharmaceutical compositions, and more particularly, to oral transmucosal pharmaceutical compositions including testosterone synergistically combined with a clomiphene-like selective estrogen receptor modulator (C-SERM) for maintaining pituitary gonadotropins within normal physiologic levels.
2. Background Information
Male testosterone deficiency is a syndrome associated with hormonal profile changes that negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Further, testosterone deficiency has been shown to be related to low quality of erections, loss of libido, osteoporosis, weight gain, muscle weakness, decreased lean body mass, diabetes mellitus, and cognitive changes. The decrease in serum testosterone levels may be due to primary testicular failure and/or dysfunction of the hypothalamic-pituitary axis. This testosterone deficiency in aging males is associated with increased body weight and adipose tissue, and changes in estrogen levels due to peripheral conversion of testosterone to estradiol. The negative feedback mechanism from excess estradiol results in a paradoxically low luteinizing hormone (LH) secretion from the pituitary despite a physiologically low testosterone level. Unfortunately, low LH secretion results in a decrease in testosterone production.
Currently, the most common treatment for symptomatic male testosterone deficiency is testosterone therapy employing various transdermal (e.g., implanted pellets, patches, gels, etc.), oral, buccal, and injectable delivery methods. These methods typically involve very high doses of testosterone. The main purpose of the testosterone replacement therapy is to achieve a normal range of testosterone serum levels.
Oral therapy of testosterone lacks effectiveness because testosterone is metabolized extensively during the first passage of the liver before reaching the systemic blood circulation (e.g., the first-pass effect). Intramuscular injections of testosterone esters are widely used, but severe drawbacks for this form of treatment include local pain, tolerability, and the unphysiologically high levels of testosterone in the body during the first days/weeks after injection. Local pain is attributed to the large volumes of testosterone injected at a specific injection site. Other drawbacks to intramuscular injections include the need for required assistance of health care professionals thereby making injections inconvenient and expensive. These same drawbacks also apply to some of the transdermal applications, such as, for example implanted pellets.
Transdermal administration (e.g., implanted pellets, patches, gels, etc.) possesses the benefits of the avoidance of the first-pass effect as well as the elimination of local pain at the injection site. Unfortunately, transdermal compositions, excluding implanted pellets, currently prescribed for hypogonadal men include from 40 mg to 120 mg daily doses of which only a low percentage is absorbed through the skin. Another drawback is that a large part of the testosterone remains on the skin with the potential risk of being transferred to another person through direct skin-to-skin contact. Additionally, the non-absorbed portion of testosterone is lost to the surrounding environment making these formulations non-environmentally-friendly. Another common side effect of transdermal compositions is local skin irritation, which is likely due to the very high ethanol content of such formulations.
Oral transmucosal delivery is a particularly advantageous delivery route because it is a non-invasive drug delivery method. Oral transmucosal delivery promotes better patient compliance and involves lower costs than invasive procedures such as injection and implantation of pellets. Oral transmucosal delivery also results in a much shorter onset time (e.g., the time from administration to therapeutic effect) than oral delivery and may be easily self-administered. Oral transmucosal administration involves the patient holding the composition within the oral cavity (e.g., between the cheek and gum, beneath the tongue, etc.) while the API dissolves in the available fluid (e.g., saliva), diffuses through the mucosa lining of the mouth, and enters the bloodstream bypassing the gastrointestinal tract as well as hepatic metabolism.
Selective Estrogen Receptor Modulators (SERMs) are structurally unique compounds that interact with intracellular estrogen receptors in target organs. SERMs can possess either antagonist or agonist properties, and in certain cases, may possess both properties. Some SERMs, such as, tamoxifen and raloxifene possess estrogen agonist properties that cause unusual pharmacological effects to be exhibited when these particular SERMs interact with certain tissues (e.g., bone, liver and cardiovascular system tissues). Additionally, these same SERMs possess estrogen antagonist properties when these particular SERMs interact with other tissues (e.g., brain and breast tissues). Finally, these same SERMs possess mixed agonist/antagonist properties when interacting with uterine tissue. Clomiphene and SERMs that mimic clomiphene, act specifically as an estrogen antagonist in the brain, specifically in the hypothalamus and pituitary sites.
Within the testosterone negative feedback mechanism, estradiol received at hypothalamus receptor sites slows down the release of GnRH from the hypothalamus which in turn results in the reduction of LH/FSH production by the pituitary gland. Estradiol received at the pituitary gland also results in the reduction of LH/FSH production by the pituitary gland. Clomiphene acts to increase the production and release of GnRH by the hypothalamus as well as production and release of LH and FSH from the pituitary gland. LH and FSH then act on the testes to increase the production of testosterone and sperm, respectively. Therefore, clomiphene-like SERMs can be used for both hypogonadism and male infertility.